Project Summary/Abstract The objective of this proposal is to predict cognitive decline in adults with Down syndrome and to ultimately provide a platform for early intervention to prevent the dementia associated with Alzheimer disease. Individuals with Down syndrome have an increased incidence of Alzheimer disease over age 40 years. Once dementia has begun, treatments appear to have little efficacy. The specific aims of this study will assess whether imaging and biomarker analysis will predict cognitive decline in adults with Down syndrome prior to the onset of dementia. Cognitive decline will be assessed using a battery of informant based and direct measures which demonstrate sensitivity to changes associated with developmental aging and dementia in Down syndrome. Specific aim 1 will determine whether quantitative EEG imaging will predict cognitive decline. When adults with Down syndrome develop seizures, the cognitive decline may become precipitous. This aim seeks to identify neurophysiological markers reflecting epilepsy and EEG disorganization as predictors of cognitive decline. The 2nd specific aim will assess whether amyloid uptake is increased in brain by positron emission tomography as a predictor of dementia. Individuals with Down syndrome have triplication of the amyloid precursor protein gene on chromosome 21. We predict that amyloid uptake will increase in those individuals with Down syndrome who go on to develop cognitive decline. The 3rd specific will examine several biomarkers that have a high likelihood of predicting cognitive decline in DS. Based upon the evidence implicating chronic oxidative stress in Down syndrome, we will focus on critical region mutations in mitochondrial DNA with the hypothesis that their number will increase in association with cognitive decline. Additionally, we shall examine 2 key chemical components of Alzheimer plaques and tangles (beta-amyloid and hyperphosporylated tau) in the cerebrospinal fluid. We predict that increased levels of hyperphosporylated tau and lower levels of beta-amyloid in cerebrospinal fluid will herald cognitive decline as has been demonstrated in patients with Alzheimer disease in the general population. This aim will also examine cerebrospinal fluid and plasma levels for inflammatory factors that have been shown to be altered in Alzheimer disease in the general population. We predict that pathological processes leading to cognitive decline in Down syndrome will trigger a characteristic signature of changes in cytokines, chemokines and growth factors in spinal fluid and plasma. The final aim of this study seeks to develop a predictive model by which the changes in imaging and biomarker measures will allow a composite assessment of the likelihood of cognitive decline. We predict that this model will form one basis for considering early intervention to prevent dementia in Down syndrome. This proposal is consistent with the mission of NICHD in directing attention towards the prevention of disease and disability in a population with a common developmental disorder.